Colfosceril, Cetyl Alcohol, and Tyloxapol (Intratracheal-Local )

VA CLASSIFICATIONPrimary: RE700

Commonly used brand name(s): Exosurf Neonatal.

Other commonly used names for colfosceril are
colfosceril palmitate, dipalmitoylphosphatidylcholine , DPPC, and synthetic lung surfactant .Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Pulmonary surfactant—

IndicationsAccepted

Respiratory distress syndrome, neonatal (prophylaxis and treatment)—Colfosceril, cetyl alcohol, and tyloxapol combination is indicated for the prophylactic treatment of infants with birth weights of less than 1350 grams who are at risk of developing respiratory distress syndrome (RDS) and of infants with birth weights greater than 1350 grams who show evidence of pulmonary immaturity. {01}{24}{26}
—Colfosceril, cetyl alcohol, and tyloxapol combination is also indicated for rescue treatment of infants who have developed RDS. {21} Infants considered for rescue treatment with this medication should be on mechanical ventilation, and have a diagnosis of RDS based on the presence of respiratory distress that is not due to causes other than RDS (as shown by clinical and laboratory assessments) and on chest radiographic findings consistent with the diagnosis of RDS. {01}{24}{26}

Natural lung surfactant is a mixture of lipids and apoproteins secreted by the alveolar cells into the alveoli and respiratory air passages. It reduces the surface tension of pulmonary fluids and thereby increases lung compliance. Surfactant exhibits not only surface tension–reducing properties (contributed by the lipids), but also rapid spreading and adsorption (contributed by the apoproteins). The major fraction of the lipid component of natural lung surfactant is dipalmitoylphosphatidylcholine (DPPC); this comprises up to 70% of the natural surfactant by weight. {01}{03}{04}{05}{06}{07}{10}{24}{26}

Although the colfosceril (also known as DPPC) contained in the synthetic protein-free lung surfactant reduces surface tension, it alone is ineffective in RDS because it spreads and adsorbs poorly due to slow dispersion at air-fluid interfaces. Cetyl alcohol acts as the spreading agent for the colfosceril at the air-fluid interface, resulting in surface-tension effects that are similar to those of endogenous lung surfactant. Tyloxapol, a polymeric long-chain repeating alcohol, is a nonionic surfactant that acts to disperse both colfosceril and cetyl alcohol. Therefore, colfosceril, cetyl alcohol, and tyloxapol combination, when used as a replacement for deficient endogenous lung surfactant, is effective in reducing the surface tension of pulmonary fluids, thereby increasing lung compliance properties in RDS to prevent alveolar collapse and decrease work in breathing. {01}{03}{04}{05}{06}{07}{24}{26} The possibility exists that it may also improve ventilation/perfusion matching, independent of its direct effect on lung compliance. {14}{15}{16}Absorption:

In nonclinical studies, it has been shown that DPPC can be absorbed from the alveolus into lung tissue where it can be catabolized extensively and reutilized for further phospholipid synthesis and secretion. However, human pharmacokinetic studies on the absorption, biotransformation, and excretion of the components of colfosceril, cetyl alcohol, and tyloxapol combination have not been performed. {01}{24}Distribution:

The lung surfactant administered endotracheally is distributed to the lung lobes, distal airways, and alveolar spaces. As the lung surfactant is distributed to the bronchi, bronchioles, and alveoli after administration in the upper airway, its concentration is highest at the alveolar air-fluid interface where it remains as a monolayer. {04}{05}

The lung surfactant does not enter systemic circulation from normal, healthy lungs; however, when the integrity of the alveolar lining is disrupted, as occurs in infants with RDS, the surfactant may be distributed outside the lungs into systemic circulation. {04}{05}

Precautions to ConsiderCarcinogenicity

Long-term studies have not been performed in animals to evaluate the carcinogenic potential of colfosceril, cetyl alcohol, and tyloxapol combination. {01}{24}Mutagenicity

Colfosceril, at concentrations up to 10,000 mcg per plate, was not mutagenic in the Ames Salmonella assay. {01}{24}Pregnancy/Reproduction
Fertility—
The effects of colfosceril, cetyl alcohol, and tyloxapol combination on fertility have not been studied. {01}{24}

Pregnancy—
No information is available on the use of colfosceril, cetyl alcohol, and tyloxapol combination during pregnancy.Breast-feeding

No information is available on the use of colfosceril, cetyl alcohol, and tyloxapol combination during breast-feeding.Pediatrics

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of colfosceril, cetyl alcohol, and tyloxapol combination in children.

Geriatrics

No information is available on the relationship of age to the effects of colfosceril, cetyl alcohol, and tyloxapol combination.Patient monitoringThe following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

(if arterial or transcutaneous carbon dioxide [CO 2] measurements are < 30 torr, ventilation {12} should be reduced at once; failure to reduce ventilator pressure or rate {12} in such cases may result in severe hypocarbia, which can cause barotrauma and {12} reduce brain blood flow {01}{24}{26})

(if the infant becomes pink and transcutaneous oxygen saturation is in excess of 95%, the fraction of inspired oxygen [F IO 2] should be reduced in small but repeated increments, until saturation is 90 to 95%, without waiting for confirmation of elevated arterial oxygen partial pressure [PaO 2] {12}{28} by blood gas assessment; failure to reduce F IO 2{12} in such cases may result in hyperoxia {01}{24}{26})

Arterial blood pressure and
Electrocardiogram (ECG) (continuous monitoring of ECG during dosing is recommended; in most infants treated prophylactically, monitoring of ECG should be initiated prior to administration of the first dose of colfosceril, cetyl alcohol, and tyloxapol combination; for subsequent doses, arterial blood pressure monitoring during dosing is also recommended {01}{24}{26})

Chest expansion and
Color and
Endotracheal tube patency and position and
Heart rate and
Oxygen saturation, transcutaneous (prior to dosing, it should be verified that the endotracheal tube tip is correctly positioned in mid-trachea {13}; also, brisk and symmetrical chest movement with each mechanical inspiration and equal breath sounds in the two axillae should be confirmed {01}{24})

(monitoring of chest expansion, color, endotracheal tube patency and position, heart rate, and transcutaneous oxygen saturation during dosing is recommended; if heart rate slows, the infant becomes dusky or agitated {12}, or the medication backs up in the endotracheal tube, dosing should be slowed or stopped and, if necessary, the peak inspiratory pressure, ventilator rate, or F IO 2 should be increased {12}{26}{28}; if transcutaneous oxygen saturation decreases during dosing, administration of the medication should be stopped and, if necessary, peak inspiratory pressure on the ventilator should be increased by 4 to 5 cm water for up to 15 to 20 {12} minutes, depending on the infant's degree of tolerance versus oxygenation/ventilation compromise; increases of F IO 2{12}{28} may also be required for 15 to 20 {12} minutes; however, rapid improvement in lung function may require immediate reduction in peak inspiratory pressure, ventilator rate, or F IO 2{01}{24}{26}{28})

(at the end of dosing, the proper position of the endotracheal tube should be confirmed by listening for equal breath sounds in the axillae; chest expansion, color, and transcutaneous oxygen saturation should also be checked; continuous monitoring of the patient for at least 30 minutes after dosing is recommended, since rapid lung function changes require immediate changes in peak inspiratory pressure, ventilator rate, or F IO 2{01}{24}{26}{28})

(if chest expansion improves substantially after dosing, peak ventilator inspiratory pressure should be reduced immediately, without waiting for confirmation of respiratory improvement by blood gas assessment; failure to reduce inspiratory ventilator pressure rapidly in such cases may result in lung overdistention and {12} pulmonary air leak {01}{24}{26})

Side/Adverse Effects

Note: In controlled clinical studies of infants receiving colfosceril, cetyl alcohol, and tyloxapol combination, there was an increased incidence in some of the conditions associated with {12} prematurity and RDS, including apnea {01}{05}{08}{10}{21} and pulmonary hemorrhage {01}{08}{09}. Hypoxia and bradycardia can occur during treatment and are directly related to the dosing procedure. {27}
Infants treated with synthetic surfactant may develop apnea because they are taken off the ventilator sooner due to their improved respiratory status. Thus, apnea is not considered a direct side effect of this medication and is, in fact, associated with a favorable rather than an untoward outcome. Apneic infants, whether or not they received colfosceril, cetyl alcohol, and tyloxapol combination, had fewer episodes of grade III intraventricular hemorrhage or periventricular echodensities or both, fewer air leaks, and better survival rates than did nonapneic infants. {17}{18}{19}{21}
Pulmonary hemorrhage occurred more frequently in infants who were younger, smaller (< 700 grams at birth), or male, or in those who had a patent ductus arteriosus; it usually occurred in the first two days of life. Infants treated with colfosceril, cetyl alcohol, and tyloxapol combination who received steroids more than 24 hours prior to delivery or indomethacin postnatally had a lower rate of pulmonary hemorrhage than other infants treated with this medication. {01}
Controlled clinical studies of infants receiving colfosceril, cetyl alcohol, and tyloxapol combination also showed a decreased incidence of pulmonary air leak and bronchopulmonary dysplasia, which are associated with mechanical ventilation in premature infants {01}{02}{04}{07}{08}{11}{20}{23}. Some studies have shown that, with rescue surfactant treatment, synthetic surfactant improved the chance of survival through 28 days without bronchopulmonary dysplasia. {21}{23}{25}
During an open uncontrolled study, colfosceril, cetyl alcohol, and tyloxapol combination decreased oxygen (O 2) saturation (³ 20%) in 6% of infants on prophylactic treatment and in 22% of infants on rescue treatment; increased O 2 saturation (³ 10%) in 5% of infants on prophylactic treatment and in 6% of infants on rescue treatment; decreased transcutaneous oxygen partial pressure (PaO 2{28} ) (³ 20 mm Hg) in 1% of infants on prophylactic treatment and in 8% of infants on rescue treatment; increased transcutaneous PO 2 (³ 20 mm Hg) in 2% of infants on prophylactic treatment and in 5% of infants on rescue treatment; decreased transcutaneous carbon dioxide partial pressure (PaCO 2{28}) (³ 20 mm Hg) in < 1% of infants on prophylactic treatment and in 1% of infants on rescue treatment; and increased transcutaneous PCO 2(³ 20 mm Hg) in 1% of infants on prophylactic treatment and in 3% of infants on rescue treatment. {01}{17}{24}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:Those indicating need for medical attentionIncidence rareApneabradycardia (< 60 beats per minute){01}{24}pulmonary air leak—due to excess ventilation caused by rapid improvement in lung{12}pulmonary hemorrhage{17}tachycardia (> 200 beats per minute){01}{24}

Those indicating need for medical attention only if they continue or are bothersomeIncidence less frequent or rareGagging{01}{24}

General Dosing Information
Colfosceril, cetyl alcohol, and tyloxapol combination should be used only by neonatologists and other clinicians who are experienced at neonatal intubation and ventilatory management. Also, instillation of this medication should be performed only by trained medical personnel experienced in airway and clinical management of unstable premature infants. Adequate personnel, facilities, equipment, and medications are required to optimize the perinatal outcome in these premature infants. In addition, continuous clinical attention should be given to all infants prior to, during, and after administration of this medication. {01}{24}

Colfosceril, cetyl alcohol, and tyloxapol combination should be administered only by instillation into the trachea. {01}{24}

To ensure accurate dosing, the current {14}{22} weight of the infant should be accurately determined. {01}{24}

Colfosceril, cetyl alcohol, and tyloxapol combination for intratracheal suspension is to be used with one of the 5 special endotracheal tube adapters with a special right-angle Luer-lock sideport, supplied by the manufacturer. The adapters are used as follows: {01}{24}
• An adapter size should be selected that corresponds to the inside diameter of the endotracheal tube.
• The adapter is inserted into the endotracheal tube with a firm push-twist motion.
• The breathing circuit ``Y'' is connected to the adapter.
• The cap is removed from the sideport on the adapter and the syringe containing the medication is attached to the sideport.
• After completion of dosing, the syringe is removed and the sideport is capped.
Colfosceril, cetyl alcohol, and tyloxapol for intratracheal suspension is administered through the sideport on the special endotracheal tube adapter without interrupting mechanical ventilation. {01}{24}

Prior to dosing with colfosceril, cetyl alcohol, and tyloxapol combination, proper placement of the endotracheal tube tip in the trachea and not in the esophagus or right or left mainstem bronchus should be confirmed. Brisk and symmetrical chest movement with each mechanical inspiration and equal breath sounds in the two axillae should also be confirmed prior to dosing. In prophylactic treatment, dosing with colfosceril, cetyl alcohol, and tyloxapol combination should not be delayed pending radiographic confirmation of the endotracheal tube tip position. In rescue treatment, bedside confirmation of the endotracheal tube tip position is usually sufficient if at least one chest radiograph subsequent to the last intubation confirms proper position of the endotracheal tube tip. If the endotracheal tube tip is too low, some lung areas could remain undosed. {01}{24}

Infants whose ventilation becomes severely impaired during or shortly after dosing may have mucous plugging of the endotracheal tube, especially if pulmonary secretions were prominent prior to administration of the medication. Therefore, prior to administration of colfosceril, cetyl alcohol, and tyloxapol combination, the infant should be suctioned to lessen the chance of mucous plugs obstructing the endotracheal tube. If endotracheal tube obstruction is suspected, and suctioning is ineffective in removing the obstruction, the blocked endotracheal tube should be replaced immediately. Following administration of colfosceril, cetyl alcohol, and tyloxapol combination, the infant should not be suctioned for 2 hours except when it is clinically necessary. {01}{24}

In infants weighing 500 to 700 grams, a single prophylactic dose of colfosceril, cetyl alcohol, and tyloxapol combination has been shown to significantly improve the fraction of inspired oxygen (F IO 2{28}) and ventilator settings, reduce pneumothorax, and reduce the incidence of death from respiratory distress syndrome (RDS), but it has also been shown to increase pulmonary hemorrhage. The effects of multiple doses of colfosceril, cetyl alcohol, and tyloxapol combination in infants in this weight group are not known; therefore, clinicians should carefully consider the potential risks and benefits of this medication in these infants. {01}{24}

Each dose is administered in two half-doses, with each half-dose being equivalent to 33.75 mg of colfosceril palmitate (2.5 mL of reconstituted suspension) per kg of body weight. Each half-dose is instilled slowly over a minimum of {17} 1 to 2 minutes (30 to 50 mechanical breaths) in small bursts timed with inspiration. After the first half-dose (the equivalent of 33.75 mg of colfosceril palmitate [2.5 mL of reconstituted suspension] per kg of body weight) is administered in the midline position, the infant's head and torso are turned 45° to the right for 30 seconds while mechanical ventilation is continued. Then the infant is returned to the midline position, and the second half-dose (the equivalent of 33.75 mg of colfosceril palmitate [2.5 mL of reconstituted suspension] per kg of body weight) is given in an identical manner. The infant's head and torso are then turned 45° to the left for 30 seconds while mechanical ventilation is continued, after which the infant is turned back to the midline position. Using these maneuvers allows gravity to assist in the lung distribution of the colfosceril, cetyl alcohol, and tyloxapol combination. {01}{24}

The dosage volume of the equivalent of 67.5 mg of colfosceril palmitate (5 mL reconstituted suspension) per kg of body weight may cause transient impairment of gas exchange by physical blockage of the airway, especially in infants on low ventilator setting. This may result in a drop in oxygen saturation during dosing, especially if these infants are on low ventilator settings prior to dosing. These transient effects may be overcome by increasing peak inspiratory pressure on the ventilator during dosing. F IO 2 may also be increased if necessary. In infants who are especially fragile or reactive to external stimuli, increasing peak inspiratory pressure just prior to dosing may minimize any transient decrease in oxygenation. {12} However, the infant should be returned to pre-dose settings within a very short time after dosing is completed. {01}{24}

Rapid administration of colfosceril, cetyl alcohol, and tyloxapol combination may cause reflux of the medication into the endotracheal tube during dosing. If reflux occurs, administration of the medication should be stopped and, if necessary, the peak inspiratory pressure on the ventilator should be increased {12} until the endotracheal tube clears. {01}{24}

In controlled clinical studies with infants receiving colfosceril, cetyl alcohol, and tyloxapol combination, infants who received steroids more than 24 hours prior to delivery or indomethacin postnatally had a lower rate of pulmonary hemorrhage than did other infants treated with this medication. Careful attention should be given to early treatment (unless contraindicated) of patent ductus arteriosus during the first 2 days of life (while the ductus arteriosus is often clinically silent).

Intratracheal Dosage FormsCOLFOSCERIL PALMITATE, CETYL ALCOHOL, AND TYLOXAPOL FOR INTRATRACHEAL SUSPENSIONUsual pediatric dose
Pulmonary surfactant (prophylaxis)
Intratracheal, the equivalent of 67.5 mg of colfosceril palmitate (5 mL of reconstituted suspension) per kg of body weight for the first dose, administered (in two half-doses) as soon as possible after birth; second and third doses (each given in two half-doses) should be administered approximately twelve and twenty-four hours later to all infants remaining on mechanical ventilation at those times. {01}{24}{26}

Pulmonary surfactant (rescue treatment)
Intratracheal, initially the equivalent of 67.5 mg of colfosceril palmitate (5 mL of reconstituted suspension) per kg of body weight administered (in two half-doses) as soon as possible after diagnosis of respiratory distress syndrome (RDS) is confirmed; a second dose (given in two half-doses) should be administered approximately twelve hours after the first dose, provided that the infant remains on mechanical ventilation. {01}{24}{26} Administration of a third or fourth dose when signs of RDS persist or recur was not shown to be of overall clinical benefit. {28}{29}{30}

Note: Each dose is administered in two half-doses, with each half-dose being equivalent to 33.75 mg of colfosceril palmitate (2.5 mL of reconstituted suspension) per kg of body weight. Each half-dose is instilled slowly over a minimum of {17} one to two minutes (thirty to fifty mechanical breaths) in small bursts timed with inspiration. {01}{24}{26}

Strength(s) usually available
U.S.—

108 mg of colfosceril palmitate, 12 mg of cetyl alcohol, and 8 mg of tyloxapol per vial (13.5 mg of colfosceril palmitate, 1.5 mg of cetyl alcohol, and 1 mg of tyloxapol per mL, when reconstituted with 8 mL of Sterile Water for Injection supplied by manufacturer) (Rx) [Exosurf Neonatal (sodium chloride 47 mg per vial)]

Canada—

108 mg of colfosceril palmitate, 12 mg of cetyl alcohol, and 8 mg of tyloxapol per vial (13.5 mg of colfosceril palmitate, 1.5 mg of cetyl alcohol, and 1 mg of tyloxapol per mL, when reconstituted with 8 mL of Sterile Water for Injection supplied by manufacturer) (Rx) [Exosurf Neonatal (sodium chloride 47 mg per vial)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.Preparation of dosage form:
Colfosceril, cetyl alcohol, and tyloxapol combination should be reconstituted immediately before use because it does not contain antibacterial preservatives. {01}{24}

Solutions containing buffers or preservatives should not be used for reconstitution; Bacteriostatic Water for Injection USP should also not be used.

Each vial of colfosceril, cetyl alcohol, and tyloxapol combination should be reconstituted only with 8 mL of the preservative-free Sterile Water for Injection provided by the manufacturer, as follows: {01}{24}{26}

• A 10- or 12-mL syringe is filled with 8 mL of preservative-free Sterile Water for Injection, using an 18- or 19-gauge needle. {01}

• The vacuum in the vial should be allowed to draw the sterile water into the vial. {01}{24}{26}

• As much of the 8 mL as possible should be aspirated out of the vial into the syringe (while maintaining the vacuum), then the syringe plunger suddenly released; this step should be repeated three or four times to assure adequate mixing of the vial contents. If a vacuum is not present, the vial of colfosceril, cetyl alcohol, and tyloxapol combination should not be used. {01}{24}{26}

• The appropriate dosage volume for the entire dose (5 mL [equivalent of 67.5 mg of colfosceril palmitate] per kg of body weight) should then be drawn into the syringe from below the froth in the vial (while maintaining the vacuum). {01}{24}{26}

• Following reconstitution, the colfosceril, cetyl alcohol, and tyloxapol combination preparation is a milky white suspension with a total volume of 8 mL per vial. {01}{24}{26}Stability:
The reconstituted suspension is chemically and physically stable and remains sterile for up to 24 {29} hours following reconstitution (using aseptic technique) {17} when stored at 2 to 30 °C (36 to 86 °F); however, the manufacturer's labeling states that it is best to reconstitute the colfosceril palmitate, cetyl alcohol, and tyloxapol combination immediately before use because the product does not contain antibacterial preservatives. {01}{24}{26}

If the suspension appears to separate, the vial should be gently shaken or swirled to resuspend the preparation. {01}{24}{26}

The reconstituted product should be inspected visually for homogeneity immediately before administration; if persistent large flakes or particulates are present, the vial should not be used. {01}{24}{26}

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